Endocrine dysfunction induced by immune checkpoint inhibitors / Disfunción endocrina inducida por inhibidores de los puntos de control inmune

Abstract Since their approval in 2011, immune checkpoint inhibitors (ICPis) are increasingly used to treat several advanced cancers. ICPis target certain cellular molecules that regulate immune response resulting in antitumor activity. The use of these new agents needs careful monitoring since they brought a whole new spectrum of adverse events. In this review, we aim to describe different endocrine dysfunctions induced by ICPis and to underline the importance of diagnosing and managing these adverse effects. Immune-related endocrine toxicities include thyroid dysfunction, hypophysitis and, less frequently, type 1 diabetes, primary ad renal insufficiency and hypoparathyroidism. Diagnosis of endocrine adverse events related to ICPis therapy can be challenging due to nonspecific manifestations in an oncological scenario and difficulties in the biochemical evaluation. Despite the fact that these endocrine adverse events could lead to life-threatening consequences, the availability of effective replacement treatment enables continuing therapy and together with an interdisciplinary approach will impact positively on survival.

Resumen Desde su aprobación en 2011, el uso de los inhibidores de los puntos de control inmunes (ICPis) se ha ex tendido para el tratamiento de diversas neoplasias en estadios avanzados. Los ICPis tienen como blanco ciertas moléculas de las células que regulan la respuesta inmune favoreciendo una actividad antitumoral. El uso de estos nuevos agentes requiere un monitoreo específico, ya que se han vinculado con un amplio y nuevo espectro de efectos adversos. El objetivo de esta revisión es describir las diferentes disfunciones endocrinas inducidas por los ICPis y destacar la importancia del diagnóstico y manejo oportuno de estos efectos adversos. Los efectos adversos inmunes endocrinos incluyen disfunción tiroidea, hipofisitis y con menor frecuencia, diabetes tipo 1, insuficiencia suprarrenal primaria e hipoparatiroidismo. El diagnóstico de eventos adversos endocrinos relacionados con la terapia ICPis es un desafío debido a su presentación clínica inespecífica en un escenario oncológico y a las dificultades en la evaluación bioquímica. Estos eventos adversos endocrinos podrían tener consecuencias potencialmente letales, pero la disponibilidad de un tratamiento de reemplazo eficaz permite continuar la terapia y, junto con un enfoque interdisciplinario, generar un impacto positivo en la supervivencia.

Clinical characteristics and diagnostic models of latent autoimmune diabetes in adults with newly diagnosed type 2 diabetes mellitus / 中国医师杂志

Objective:To analyze the clinical features of latent autoimmune diabetes (LADA) in adults among newly diagnosed type 2 diabetes mellitus (T2DM), and to explore whether LADA diagnostic models can be established based on this.Methods:From May 2016 to January 2017, 302 patients with newly diagnosed T2DM in the outpatient and inpatient department of metabolism and endocrinology of Yueyang Central Hospital were analyzed. All of them were tested for glutamic acid decarboxylase antibody (GADA). According to the consensus of the Chinese Medical Association Diabetes Association (CDS) LADA diagnosis and treatment, they were divided into LADA group (18 cases) and T2DM group (284 cases). The general clinical data and clinical biochemical indexes of the two groups were analyzed; Multiple linear regression method was used to evaluate the feasibility of establishing LADA diagnostic model.Results:⑴ Compared with patients in the T2DM group, the patients in the LADA group had a younger age of onset, and " three more and one less" symptoms were more common ( P<0.05); the weight, body mass index (BMI), waist circumference, waist-to-hip ratio (WHR), triglycerides (TG), fasting C peptide (FCP), postprandial 2 h C peptide (2 h-CP), modified islet function index HOMA-islet (CP-DM), and modified insulin resistance index HOMA-IR (CP) in the LADA group were all lower, while high-density lipoprotein cholesterol (HDL-C) and HbA1c were higher ( P<0.05). ⑵ the linear regression method was used to analyze the multicollinearity of patients in LADA group and T2DM group. The biochemical indexes with statistically significant difference were selected as independent variables through correlation analysis, and the GADA value was used as dependent variable. The statistical results showed that the independent variables could not fully meet the conditions of multicollinearity regression analysis. Conclusions:⑴ Related clinical features and glucose metabolism indicators have differential diagnosis significance for LADA, but this study cannot be used for multiple linear regression analysis, and it is difficult to establish a diagnostic model for LADA. ⑵ LADA diagnosis is a comprehensive diagnosis, which should be combined with the results of islet autoantibody and clinical features.

Low rate of latent autoimmune diabetes in adults (LADA) in patients followed for type 2 diabetes: A single centers experience in Turkey

ABSTRACT Objective In this study, we aimed to determine the frequency of and the clinical and metabolic features of patients with latent autoimmune diabetes in adults (LADA) at a single center in Turkey. Subjects and methods Patients over 30 years of age diagnosed with type 2 diabetes who did not require insulin for a minimum of 6 months following diagnosis were included. Data from 324 patients (163 women; 161 men), with a mean age of 54.97 ± 7.53 years, were analyzed in the study. Levels of antibodies to glutamate decarboxylase (anti-GAD) were measured in all patients, and LADA was diagnosed in patients testing positive for anti-GAD antibodies. Results Anti-GAD positivity was identified in 5 patients (1.5%). Family history of diabetes, body mass index (BMI), age, sex distribution, insulin resistance, serum triglycerides, high-density lipoprotein, and low-density lipoprotein were similar in the LADA and type 2 diabetes patients. Median HbA1c was significantly higher (10.8% vs. 7.38%, p = 0.002) and fasting C-peptide was lower (0.75 ng/mL vs. 2.82 ng/mL, p = 0.009) in patients with LADA compared to in those with type 2 diabetes. Among the 5 patients with LADA, 4 were positive for antithyroid peroxidase antibodies. The median disease duration was relatively shorter among patients with LADA (4 years vs. 7 years, p = 0.105). Conclusion We observed a LADA frequency of 1.5% among Turkish patients followed for type 2 diabetes. The presence of obesity and metabolic syndrome did not exclude LADA, and patients with LADA had worse glycemic control than patients with type 2 diabetes did.

Endocrinopatías por inmunoterapia oncológica / Endocrinopathies by oncological immunotherapy

La relación entre inmunidad y cáncer es compleja. Las células tumorales desarrollan mecanismos de evasión a las respuestas del sistema inmunitario. Esta capacidad permite su supervivencia y crecimiento. La inmunoterapia ha transformado el tratamiento oncológico mejorando la respuesta inmunitaria contra la célula tumoral. Esta se basa en el bloqueo de los puntos de control inmunitario mediante anticuerpos monoclonales contra la molécula inhibidora CTLA-4 (antígeno 4 del linfocito T citotóxico [CTLA-4]) y la proteína 1 de muerte celular programada y su ligando (PD-1/PD-L1). Aunque los inhibidores de los puntos de control inmunitario (ICIs) son fármacos bien tolerados, tienen un perfil de efectos adversos conocido como eventos adversos inmunorrelacionados (EAI). Estos afectan varios sistemas, incluyendo las glándulas endocrinas. Los eventos adversos endocrinos más frecuentes son la disfunción tiroidea, la insuficiencia hipofisaria, la diabetes mellitus autoinmune y la insuficiencia suprarrenal primaria. El creciente conocimiento de estos efectos adversos endocrinos ha llevado a estrategias de tratamiento efectivo con el reemplazo hormonal correspondiente. El objetivo de esta revisión es reconocer la incidencia de estas nuevas endocrinopatías, la fisiopatología, su valoración clínica y el manejo terapéutico. (AU)

The relationship between immunity and cancer is complex. Tumor cells develop evasion mechanisms to the immune system responses. This ability allows their survival and progression. Immunotherapy has transformed cancer treatment by improving the immune response against tumor cells. This is achieved by blocking immune checkpoints with monoclonal antibodies against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 and its ligand (PD-1 / PD-L1). Although the immune checkpoint inhibitors (ICIs) are well tolerated drugs, they have a profile of adverse effects known as immune-related adverse events (irAES). These involve diverse systems, including the endocrine glands. The most frequent endocrine immune-related adverse events are thyroid and pituitary dysfunction, autoimmune diabetes mellitus and primary adrenal insufficiency. The increasing knowledge of these irAES has led to effective treatment strategies with the corresponding hormonal replacement. The objective of this review is to recognize the incidence of these new endocrinopathies, the physiopathology, their clinical evaluation, and therapeutic management. (AU)

Analysis of the correlation between IL-23, IL-17and β-cell function in latent autoimmune diabetes in adult patients / 中国医师杂志

Objective To determine interleukin (IL)-23 and IL-17 level in latent autoimmune diabetes in adult (LADA) patients,and to explore the relationship of IL-23,IL-17and β-cell function in these patients.Methods Forty LADA patients from 2011 to 2016 in our hospital were selected as LADA group,and forty participants were as normal control group.Clinical and biochemical data was collected and the level of the IL-23 and IL-17 was measured with the enzyme linked immunosorbent assay (ELISA).The differences in interleukin levels among the two groups were compared.Pearson correlation analysis was used for investigating the relationship between the dependent of statistical significant interleukins and the independent data in the LADA patients,all closely related variables then were included in a stepwise multiple linear regression analysis.Results The levels of serum IL-23,IL-17 and IL-23/IL-17 were significantly higher in LADA group than those in control groups [3.54 (2.88 ～ 5.24) μg/L vs 1.98 (1.62 ～ 2.18) μg/L,P ＜0.05],[22.42 (17.71 ～ 26.07) ng/L vs 17.97 (17.15 ～ 20.70) ng/L,P ＜ 0.05],(175.79 ± 38.67 vs 105.22 ± 19.08,P ＜0.01).IL-23 and IL-17 in the LADA group were negatively correlated with fasting C peptide (FCP) (r =-0.42,r =-0.48,P ＜ 0.05),and the ratio of IL-23/IL-17 was positively correlated with fasting plasma glucose (FPG) (r =0.44,P =0.00).Stepwise multiple liner regression analysis showed that serum IL-23 and IL-17 level were independently associated with the FCP in LADA group.Conclusions IL-23 and IL-17 were possibly important proinflammatory factor in LADA patients,and can provide the new immunodiagnosis markers for LADA.

Analysis of the correlation between IL-23, IL-17and β-cell function in latent autoimmune diabetes in adult patients / 中国医师杂志

Objective@#To determine interleukin (IL)-23 and IL-17 level in latent autoimmune diabetes in adult (LADA) patients, and to explore the relationship of IL-23, IL-17and β-cell function in these patients.@*Methods@#Forty LADA patients from 2011 to 2016 in our hospital were selected as LADA group, and forty participants were as normal control group. Clinical and biochemical data was collected and the level of the IL-23 and IL-17 was measured with the enzyme linked immunosorbent assay (ELISA). The differences in interleukin levels among the two groups were compared. Pearson correlation analysis was used for investigating the relationship between the dependent of statistical significant interleukins and the independent data in the LADA patients, all closely related variables then were included in a stepwise multiple linear regression analysis.@*Results@#The levels of serum IL-23 , IL-17 and IL-23/IL-17 were significantly higher in LADA group than those in control groups [3.54(2.88~5.24)μg/L vs 1.98(1.62~2.18)μg/L, P<0.05], [22.42(17.71~26.07)ng/L vs 17.97(17.15~20.70)ng/L, P<0.05], (175.79±38.67 vs 105.22±19.08, P<0.01). IL-23 and IL-17 in the LADA group were negatively correlated with fasting C peptide (FCP) (r=-0.42, r=-0.48, P<0.05), and the ratio of IL-23/IL-17 was positively correlated with fasting plasma glucose (FPG) (r=0.44, P=0.00). Stepwise multiple liner regression analysis showed that serum IL-23 and IL-17 level were independently associated with the FCP in LADA group.@*Conclusions@#IL-23 and IL-17 were possibly important proinflammatory factor in LADA patients, and can provide the new immunodiagnosis markers for LADA.

Expression of miR-142 and miR-143 in peripheral blood mononuclear cells from patients with autoimmune diabetes / 中华内分泌代谢杂志

Objective To investigate the microRNA ( miRNA ) expression level of peripheral blood mononuclear cell ( PBMC) in autoimmune diabetes mellitus ( ADM) which includes type 1 diabetes mellitus ( T1DM) and latent autoimmune diabetes in adults ( LADA ) , T2DM patients, and matched healthy individuals. Methods Patients of T1DM, LADA, and T2DM were recruited in the Second Xiangya Hospital of Central South University from January 2015 to December 2016. The subjects were divided into two groups. The first group was used for high-throughput screening of differentially expressed microRNAs. The second group was used to validate the expression of miR-142-5p and miR-143-3p by real-time quantitative polymerase chain reaction (RT-qPCR). Results (1)The different miRNA expression patterns of PBMC were found among T1DM patients, LADA patients, T2DM patients, and health individuals. ( 2) Compared with T2DM patients and healthy controls, LADA and T1DM patients had down-regulated PBMC miR-142-5p expression, and up-regulated miR-143-3p expression. (3)RT-qPCR validation showed that the expression of miR-142-5p in LADA patients was significantly lower than that in T2DM patients (0.30±0.24 vs 1.33 ± 1.29, P<0.05) . The expression of miR-143-3p in T1DM and LADA was higher than that in T2DM and health individuals. However, no significant differences were found. Conclusion The miRNA expression patterns are different in the PBMC of T1DM patients, LADA patients, T2DM patients, and healthy individuals; the abnormal expressions of miR-142-5p and miR-143-3p may participate in the development of ADM by affecting apoptosis and immune cell differentiation.

Analysis of 2 cases of diabetic ketoacidosis / 中华内分泌代谢杂志

Diabetic ketoacidosis ( DKA ) is one of the common endocrine emergencies. With the development and applications of new drugs, the inducing causes of DKA become more and more complicated. We as clinicians should quickly and accurately evaluute the severity of DKA, and administrate reasonable rehydration and hypoglycemic treatment. What we should do better is searching the causes of DKA and help patients reasonably avoid its occurrence. In this article, two cases from clinical practice are analyzed.

Latent Autoimmune Diabetes in Adults: Current Status and New Horizons

Autoimmune diabetes is a heterogeneous disease which can arise at any age. Subjects with adult-onset autoimmune diabetes who do not necessitate insulin-therapy for at least 6 months after diagnosis are demarcated as having latent autoimmune diabetes in adults (LADA). This condition is more heterogeneous than young-onset autoimmune diabetes and shares clinical and metabolic characteristics with both type 2 and type 1 diabetes. Patients with LADA are considered by having highly variable β-cell destruction, different degrees of insulin resistance and heterogeneous titre and pattern of islet autoantibody, suggesting different pathophysiological pathways partially explaining the heterogeneous phenotypes of LADA. To date the heterogeneity of LADA does not allow to establish a priori treatment algorithm and no specific guidelines for LADA therapy are available. These subjects are mostly treated as affected by type 2 diabetes, a factor that might lead to the progression to insulin-dependency quickly. A personalised medicine approach is necessary to attain optimal metabolic control and preserve β-cell function to decrease the risk of long-term diabetes complications. Recent data concerning the use of oral antidiabetic agents as dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists indicate up-and-coming results in term of protect C-peptide levels and improving glycaemic control. This review summarises current knowledge on LADA, emphasising controversies regarding its pathophysiology and clinical features. Moreover, we discuss data available about novel therapeutic approaches that can be considered for prevention of β-cell loss in LADA.

Latent Autoimmune Diabetes in Adults: A Review on Clinical Implications and Management

Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease characterized by a less intensive autoimmune process and a broad clinical phenotype compared to classical type 1 diabetes mellitus (T1DM), sharing features with both type 2 diabetes mellitus (T2DM) and T1DM. Since patients affected by LADA are initially insulin independent and recognizable only by testing for islet-cell autoantibodies, it could be difficult to identify LADA in clinical setting and a high misdiagnosis rate still remains among patients with T2DM. Ideally, islet-cell autoantibodies screening should be performed in subjects with newly diagnosed T2DM, ensuring a closer monitoring of those resulted positive and avoiding treatment of hyperglycaemia which might increase the rate of β-cells loss. Thus, since the autoimmune process in LADA seems to be slower than in classical T1DM, there is a wider window for new therapeutic interventions that may slow down β-cell failure. This review summarizes the current understanding of LADA, by evaluating data from most recent studies, the actual gaps in diagnosis and management. Finally, we critically highlight and discuss novel findings and future perspectives on the therapeutic approach in LADA.

Clinical Analysis of Newly Diagnosed Diabetes Mellitus Patients by Abnormal Fundus Examination

PURPOSE: To investigate the clinical analysis of newly diagnosed diabetes mellitus (NDM) patients with abnormal fundus examination at the first visit. METHODS: This retrospective study utilized the first visit medical records of 15 patients (30 eyes) who were diagnosed with NDM from February 2011 to October 2016. RESULTS: Patients were divided into 3 groups: 1) diabetic retinopathy group including proliferative diabetic retinopathy (PDR) (3) and severe non-proliferative diabetic retinopathy (NPDR) (1); 2) retinal vascular disease group including central retinal vein occlusion (CRVO) (1), branch retinal vein occlusion (1), vitreous hemorrhage with CRVO (1) and macular edema (1); and 3) other retinal disease group including vitreous hemorrhage due to choroidal neovascular rupture (1), exudative age-related macular degeneration (3), central serous chorioretinopathy (2), and macular hole (1). All 3 PDR patients had latent autoimmune diabetes in adults (type 1.5 diabetes). The remaining 12 patients had type 2 diabetes. Three patients showed mild NPDR in the opposite eye and the other 9 patients did not have diabetic retinopathy in the opposite eye. Onset age, HbA1C and proteinuria were significantly different between the diabetic retinopathy group and the other retinal disease group (p = 0.006, p = 0.012 and p = 0.006, Mann-Whitney test). CONCLUSIONS: In patients with various retinal diseases, early detection of NDM could be achieved by performing fundoscopic imaging and systemic examination as well as basic ophthalmologic examination. In addition, patients with diabetic retinopathy should be treated promptly through ophthalmology and internal medicine consultation. For the retinal vascular disease and other retinal disease groups, not only treatment for ophthalmic diseases, but also education about diabetes treatment are important.

Relationship between B10 cells and incidence of autoimmune diabetes in non-obese diabetic mice / 中国免疫学杂志

Objective:To study relationship between B10 cells and the incidence of autoimmune diabetes in nonobese diabetic mice. Methods:20 NOD/LT female mice of 6 week old were cultured in normal culture to 30 weeks,and the mice were divided into two groups according the mice’s blood glucose,serum creatinine and body weight detected at their 30 weeks old. IL-10 levels in spleen tissues of the two groups were detected by enzyme-linked immunosorbent assay. We used flow cytometry to detect the proportion of B10 cells in the spleen of mice in the two groups. NOD/LT mice were randomly divided into control group and B10 group. The B10 cells were inoculated in B10 groups,their blood glucose were detected when they were 10,15,20,25 and 30 weeks old. Results: The blood glucose and serum creatinine levels were significantly higher in the group than that in the autoimmune diabetes group (P< 0. 05),and the body weight was significantly lower than that in the autoimmune diabetes group (P<0. 05). The level of IL-10 in the spleen tissues of the autoimmune diabetes mice was significantly higher than that in the non autoimmune diabetes group. The content of B10 cells in the spleen of the mice with autoimmune diabetes mellitus was significantly higher than that in the non autoimmune diabetes group. When mice at the age of 10,15 weeks,the incidence of autoimmune diabetes in B10 group was significantly lower than that in the control group,but the incidence of autoimmune diabetes in B10 group was significantly higher than that in control group at 20,25 and 30 weeks. Conclusion:The over accumulation of B10 cells may be one of the reasons for the further development of autoimmune diabetes in NOD mice.

The level of plasma prekallikrein and its correlation with latent autoimmune diabetes in adults / 重庆医学

Objective To investigate the plasma expression of plasma prekallikrein(KLKB1)in latent autoimmune diabetes in a‐dults(LADA),type1diabetes(T1DM),type2diabetes(T2DM)andhealthypeople,anditsrelationshipwithLADAincombination with other indicators .Methods Among the four groups ,KLKB1 ,glycosylated hemoglobin(HbA1c) ,fasting blood glucose(FPG) ,2 h postprandial plasma glucose(2 h PG) ,Fasting c‐peptide(FCP) ,2 h postprandial C peptide(2 h CP) ,and glutamic acid decarboxy‐lase antibody(GADA)were detected respectively .And the detection results were analyzed by statistics .Results By comparison , there were statistically significant difference between LADA group and other groups on FPG(except for T2DM group) ,2 h PG , HbA1c ,FCP and 2 h CP(P0 .05) .Receiver operating characteristic (ROC) showed that only using KLKB1 to di‐agnose LADA had its limitation .Conclusion KLKB1 could be used as a clinical indicator to predict the onset of LADA to a certain degree .We could screen for LADA by using KLKB1 and other indicators in people at high risk .

Cloning,Expression and Diagnostic Application of Different Fragments of Human Carboxypeptidase / 现代检验医学杂志

Objective To obtain different fragments of human carboxypeptidase H,and evaluate the diagnostic application of the recombination carboxypeptidase H in detecting autoantibody.Methods The coding gene of carboxypeptidase H was ob-tained by RT-PCR.The corresponding prokaryotic expression vectors were constructed and transformed into E.coli to in-duce the expression of the recombination different fragments of carboxypeptidase H.Using these antigen fragments as the coating antigens,the enzyme-linked immunosorbent assay (ELISA)was established for the detection of carboxypeptidase H autoantibody in 95 newly diagnosed type 2 diabetes patients.Results Three fragments of human carboxypeptidase H were obtained,in which the 42~476aa fragment antigen was ideal one.Using the full-length carboxypeptidase H as coating anti-gen,the positive rate of carboxypeptidase H autoantibody was 8.42%.Conclusion Because of the favorable antigenicity,the 42~476aa fragment antigen of carboxypeptidase H could be the candidate antigen for discrimination and diagnosis of latent autoimmune diabetes in adults.

Role of Detecting GADA and ZnT8A in Newly Diagnosed Type 2 Diabetes Patients / 现代检验医学杂志

Objective To analysis the positive rates of glutamic acid decarboxylase autoantibody (GADA)and zinc transporter 8 autoantibody (ZnT8A)in newly diagnosed type 2 diabetes patients.Methods GADA and ZnT8A were detected in 101 ca-ses of newly diagnosed type 2 diabetes mellitus patients using ELISA.Results The positive rate of GADA was 21.78%,the positive rate of ZnT8A was 17.82%,and the common positive rate of GADA and ZnT8A was 8.91%.There were no corre-lations between GADA or ZnT8A autoantibodies and the patient’s sex (t=-0.724,-0.550;0.903,1.359,P >0.05),age (t=-0.724,-0.550;0.903,1.359,P >0.05),blood glucose (r=0.290,0.110;-0.264,-0.047,P >0.05),cholesterol (r=-0.047,0.004;0.154,-0.138,P >0.05),triglyceride (r=-0.092,-0.054;-0.217,-0.023,P >0.05),and low density lipoprotein (r= - 0.045,- 0.027;0.202,- 0.025,P > 0.05).Conclusion It should be screened autoantibodies timely for newly diagnosed type 2 diabetic patients in order to diagnosis the Latent autoimmune diabetes in adults early.

Clinical Heterogeneity of Diabetes in Young Korean Patients / 임상당뇨병

Diabetes among young patients in Korea is caused by a complex set of factors. In addition to the typical T1aD and T2D patients, there is a variable incidence of cases of non-autoimmune types of T1D associated with insulin deficiency (T1b), such as fulminant T1D (FT1D). Although T1a is the major type of childhood diabetes, FT1D exists as a hyper-acute subtype of T1D that affects older children, without causing autoimmunity. They showed a complete loss of beta-cell secretory capacity without evidence of recovery, necessitating long-term treatment with insulin. In addition, latent autoimmune diabetes in adults (LADA) is a form of autoimmune-mediated diabetes, usually diagnosed based on GAD autoantibody positivity. Although many epidemiological surveys of LADA have been conducted in Caucasian and Asian populations, their reported prevalence rates vary due to the use of different diagnostic criteria. In a recent study with a comparable design and valid methodology, the prevalence of LADA using GAD autoantibody positivity as the diagnostic criterion was higher (4.4%) than the previously reported prevalence of 1.7% in a population-based T2D survey. After 36 months of follow-up, only 3 of the 39 patients initially diagnosed with LADA had become insulin-dependent, and they were all positive for multiple autoantibodies (GAD, IA-2 and ZnT8 antibody). This demonstrates that true insulin dependency, which was initially indicated by multiple antibody positivity, has not increased in the Korean population. Therefore, despite etiological heterogeneity, in the clinical setting, early diagnosis and classification of patients with diabetes relying on clinical grounds without measuring autoantibodies could be a possible method to minimize complications.

Clinical Significance of Plasma Protease C1 Inhibitor in Latent Autoimmune Diabetes in Adults / 天津医药

Objective To examine plasma levels of protease C1 inhibitor (SERPING1) in adult patients with latent autoimmune diabetes (LADA), and their clinical significance thereof. Methods The levels of SERPING1 were detected and compared between LADA, type 1 diabetes (T1DM), type 2 diabetes (T2DM) and healthy control groups. The correlation between plasma levels of SERPING1 and other clinical indicators such as age, disease course, glycosylated hemoglobin (HbA1c), fasting blood glucose (FPG), 2 h postprandial plasma glucose (2 hPG), fasting c-peptide (FCP) and 2 h postprandi-al C peptide (2 hCP) was analyzed. Multi-factor regression analysis and receiver operating characteristic (ROC) were used to evaluate the predictive effect of SERPING1 in LADA at the early stage. Results The level of SERPING1 was significantly higher in LADA group than that of T2DM group and control group (P < 0.05). There was a negative correlation between SERPING1 and FCP, and a positive correlation between SERPING1 and HbA1c, FPG and 2 hPG (P<0.05). There were no significant correlation between SERPING1 and age, disease course and 2 hCP. FCP was analyzed by regression equation (P<0.05), and which was the main influence factor of the plasma level of SERPING1. The area under the ROC curve (AUC) of SERPING1 was 0.613 (P<0.05), 95%CI 0.514-0.712. The optimal cut-point of SERPING1 for early prediction of LADA was 289.71 mg/L, and the sensitivity and specificity were 69%and 48%respectively. Conclusion SERPING1 combined with other indicators will be useful for identifying LADA from T2DM at the early stage.

A Latent Autoimmune Diabetes in Adults Patient Manifesting Severe Musculoskeletal Complications

Patients with diabetes have many different kinds of complications involving multiple organs, but those involving the musculoskeletal system are relatively uncommon. Diabetic muscle infarction (DMI) is a rare, painful, and potentially serious condition in patients with poorly controlled diabetes mellitus. A 35-year-old man diagnosed with type 2 diabetes eight years ago, visited with severe muscle pain in the right anteromedial thigh without any event of trauma. He had been treated with metformin, but his glycemic control was very poor with a glycated hemoglobin of 14.5%. Evaluation of his painful thigh lesion did not reveal any evidence of infection or vasculitis, but the magnetic resonance imaging and bone scan showed findings of DMI at vastus medialis muscle and an insufficiency fracture at the right medial tibial condyle. He was diagnosed with retinopathy, neuropathy and microalbuminuria but not macrovascular complications. We also diagnosed his diabetes as latent autoimmune diabetes in adults (LADA) based on his low C-peptide level, positive anti-glutamic acid decarboxylase (GAD) antibody and early onset diabetes. Instead of antibiotics, bed rest, analgesics and strict blood glucose control with multiple daily insulin injections led to symptom improvement. This is an unusual case of a young man with LADA experiencing severe musculoskeletal complication of DMI and insufficiency fracture. If a poorly controlled diabetic patient appears to have unaccounted soft tissue pain, musculoskeletal complications such as DMI associated with hyperglycemia should be considered.

Detection of carboxypeptidase H specific T cells in peripheral blood of latent autoimmune diabetic patients with carboxypeptidase antibody positivity by ELISPOT assay / 中南大学学报(医学版)

Objective To explore the characteristics of T cell immunity in peripheral blood of patients with carboxypeptidase - H antibody (CPH-Ab). Methods Forty-two latent autoimmune diabetes in adults (LADA) patients with CPH-Ab~+ alone, 20 Type 2 diabetes mellitus patients (T2DM), and 22 healthy controls were selected and their peripheral blood mononuclear cells were isolated. Human recombinant carboxypeptidase (CPH) protein was expressed and further used as a stimulant in Enzyme-linked immunospot (ELISPOT) assay to detect IFN-γ-Th1 and IL-4-Th2 cells in the 3 groups. Th1/Th2 ratios were also calculated. CPH-Ab and glutamic acid decarboxylase antibody (GAD-Ab) were determined by radioligand assay. Results Compared with healthy controls and T2DM, IFN-γ-Th1 and IL-4-Th2 numbers did not increase significantly in CPH-Ab~+ group, nor did the Th1/Th2 ratios (P ＞0. 05). We further divided the CPH-Ab~+ patients into a short duration group (n = 22) and a long duration subgroup (n = 20) according to the duration of 3 years. CPH-IL-4-T in the short duration subgroup was significantly higher than that in T2DM and healthy controls (1. 8 vs. 0.2 and 0.3, both P ＜ 0. 05) and we did not find any factor that was significantly correlated with the IL-4 spots number. There were not any significant differences in T cell responses to phaseolus vulgaris agglutinin (PHA) among all groups (P＞0.05). Conclusion CPH does not directly involve in the cellular pathological mechanism of LADA. Anti-CPH immunity may be associated with more slowly aggressive beta cell autoimmunity.

Evaluation of subclinical left ventricular systolic and diastolic function with velocity vector imaging in patients with latent autoimmune diabetes in adults / 中南大学学报(医学版)

Objective To assess subclinical left ventricular systolic and diastolic function in normotensive latent autoimmune diabetes in adult (LADA) patients with normal ejection fraction and fractional shortening by velocity vector imaging (VVI) . Methods Digital dynamic imaging of 60 normotensive LADA patients and another 60 healthy subjects were collected. The longitudinal velocity, strain, and strain rate were measured in systolic, early and later diastolic period respectively and the peak time of velocity, strain, and strain rate were recorded. The parameters were analyzed. Results Compared with the control group, all of the measured parameters of LADA patients were significantly lower (P ＜ 0. 01), except the later diastolic strain (P ＞ 0. 05) . The peak time of myo-cardial longitudinal velocity, strain and strain rate was lengthened compared with the control group, but without statistical significance (P ＞ 0. 05). Conclusion VVI is a novel and noninvasive tool to quantitatively and objectively assess left ventricular regional systolic and diastolic function in the LADA patients. It can make trustworthy early diagnose of abnormal left ventricle myocardial performance in patients with subclinical LADA.